Two principal Immunopathogenetic features characterize the autoimmune inflammatory myopathies - polymyositis, dermatomyositis, and related diseases: lymphocytic destruction of muscle cells, and humoral autoimmunity distinguished by a striking set of disease-specific autoantibodies. Although the muscle cell destruction is mediated by lymphocytes, the autoantibodies, particularly those directed against the family of functionally related but structurally diverse aminoacyl-tRNA synthetases, seem to offer a useful window on the disease and have been the focus of much of this group?s research for a number of years. Work continues, although at a diminished intensity, on the humoral autoimmunity. The goal of these studies is to design better ways to treat myositis Recently our attention has focused on the lymphocytic destruction and death of muscle cells. The tissue damage in myositis, in contract to the majority of autoimmune tissue damage, is associated with a predominantly CD-8+ infiltrate. Furthermore, muscle is one of the few tissues in which MHC Class I is constitutively absent, but in myositis, it is markedly up-regulated on myocytes, raising the possibility that this up-regulation plays a role in initiating and sustaining the inflammation. The following areas have been pursued this year: 1) Studies of the synthesis of cytokines, immune co-stimulatory molecules, and MHC by myocytes in response to inflammatory stimuli have shown that muscles cells both respond to and can synthesize cytokines in response to inflammatory stimuli, thereby establishing a much more active role for muscle in controlling immune attack. They have also shown that MHC I is up-regulated in response to such stimulation in vitro. But most strikingly, the co-stimulatory molecules CTLA4 and CD28, previously known only to be expressed on lymphocytes, were induced on the surface of cultured human myoblasts by proinflammatory cytokines. Furthermore, they could also be seen on the surface of muscle cells by immunohistochemical staining of muscle biopsies from patients with myositis but not from controls. 2) In studies in collaboration with the Rosen group at Johns Hopkins, we have confirmed the apparent absence of apoptosis in biopsies from patients with myositis despite the presence of both FAS and FAS-L. On-going studies with cultured muscle cells have shown that even with the up-regulation of FAS by pro-inflammatory stimuli, anti-FAS antibodies cannot induce apoptosis. Of considerable interest is the fact that the anti-apoptotic molecule, FLIP, was upregulated in stimulated cells. 3) Transgenic mice in which MHC Class I is constitutively up-regulated or is up-regulated in skeletal muscle only, or can be up or down-regulated by the feeding of tetracycline have been made or are currently being bred to determine whether MHC up-regulation incites inflammation as has done in several other systems. 4) The effect of methimazole, an anti-thyroid drug which down-regulated Class I in rodents, is being studied on cultured muscle cells and on Class I of muscle and lymphocytes in patients receiving the drug in a therapeutic trial (see Z01 AR 41076-08 ARB). These studies, which are being performed in the lab of Dr. Leonard Kohn of NIDDK by Dr. N. Shafran, a fellow in ARB, are also being used to explore the usefulness of methimazole congeners which also affect MHC regulation.